Abstract 420: Combination of the MCL1 inhibitor PRT1419 and SMARCA2 degrader PRT3789 shows combinatorial benefit in SMARCA4 deleted lung cancer
Authors: Norman Fultang, Neha Bhagwat, Diane Heiser, Alexander Grego, Michael Hulse, Venkat Thodima, Koichi Ito, Kris Vaddi, Bruce Ruggeri, Peggy Scherle
Journal: Cancer Research (2022)

Abstract MCL1 is a member of the anti-apoptotic BCL2 family of proteins and plays a critical role in maintaining cellular homeostasis and promoting cell survival. MCL1 amplifications occur frequently in multiple tumor types. It has also been implicated in mediating resistance to chemotherapeutic agents and targeted therapies. We have previously described a novel, potent and orally bioavailable MCL1 inhibitor, PRT1419, that demonstrates anti-tumor efficacy in various preclinical models of cancer and is currently under evaluation in a Phase I clinical trial in patients with relapsed/refractory hematologic malignancies and advanced solid tumors. In an effort to identify novel biomarkers that might predict sensitivity to MCL1 inhibition, we conducted a gene dependency analysis using publicly available human cancer cell line data generated from genome-wide CRISPR/Cas9-mediated cell viability screens. We observed that mutations in the SWI/SNF complex, particularly in lung and ovarian cancer cell lines, conferred a strong functional dependency on MCL1. The mammalian SWI/SNF complex functions as a tumor suppressor in a number of cancers and regulates gene expression via chromatin-remodeling. It is comprised of multiple subunits, including one of two catalytic ATPases (SMARCA2 or SMARAC4), DNA-binding proteins ARID1A, ARID1B and ARID2, and other chromatin-binding subunits. Gene mutations in members of this complex occur in &amp;gt;20% of human cancers, and therapeutic agents targeting its function are under active clinical investigation. We and others have shown potent synthetic lethality with the use of SMARCA2 targeted protein degraders in SMARCA4 deleted lung cancer models. A previously published genome-wide CRISPR screen in SMARCA4-mut lung cancer cell lines demonstrated that loss of MCL1 could sensitize these cells to SMARCA2 degradation. Therefore, we evaluated PRT1419 in combination with a novel and selective SMARCA2 degrader, PRT3789, in SMARCA4 deleted lung cancer models. We observed a potent synergistic interaction in SMARCA4 deleted cell lines in vitro, whereas no additive benefit was seen in SMARCA4 WT lines. Further, combining PRT1419 and PRT3789 in vivo in cell line-derived xenograft models resulted in significant tumor growth inhibition, including tumor regressions. Additionally, we profiled PRT1419 ex vivo in a panel of lung cancer PDX models and observed significant, dose-dependent effects on cell viability in SMARCA4 deleted models with low SMARCA2 expression. In a broader lung cancer cell line viability screen conducted with PRT1419, we observed that the presence of multiple, co-occurring alterations in SWI/SNF family members such as SMARCA4, ARID1A/B mutations and loss of SMARCA2 protein were associated with sensitivity to PRT1419. Based on these findings, preclinical evaluation of PRT1419 in other tumor types with recurrent SWI/SNF mutations is ongoing. Citation Format: Norman Fultang, Neha Bhagwat, Diane Heiser, Alexander Grego, Michael Hulse, Venkat Thodima, Koichi Ito, Kris Vaddi, Bruce Ruggeri, Peggy Scherle. Combination of the MCL1 inhibitor PRT1419 and SMARCA2 degrader PRT3789 shows combinatorial benefit in SMARCA4 deleted lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 420.